1. Field of the Invention
The invention relates generally to the technology of noninvasive analyte determination in the human body. More particularly, the invention relates to the use of a placement guide in conjunction with a diffuse reflectance based near-IR glucose analyzer. The placement guide couples to a glucose analyzer and has at least one of a hydration inducer and a reservoir for a coupling agent used for automatic or manual delivery of the coupling agent to the sampling site.
2. Description of Related Art
Spectroscopy based noninvasive analyzers deliver external energy in the form of light or rays to a specific sampling site or region of the human body where the photons interact with the chemistry and physiology of the sampled tissue. A portion of the incident photons are scattered or transmitted out of the body where they are detected. Based upon knowledge of the incident photons and detected photons, the chemical and/or structural basis of the sampled site may be deduced. Several distinct advantages to a noninvasive system are the analyses of chemical and structural constituents in the body without the generation of a biohazard in a pain free manner with limited consumables. The technique may also allow for multiple analytes or structural features to be determined at one time. Some common examples of noninvasive analyzers are magnetic resonance imaging (MRI), X-rays, pulse oximeters, and noninvasive glucose analyzers. With the exception of X-rays, these determinations are performed with relatively harmless wavelengths of radiation. Examples herein focus on noninvasive glucose determination, but the principles apply to other modes of noninvasive analyses.
Diabetes
Diabetes is a chronic disease that results in improper production and utilization of insulin, a hormone that facilitates glucose uptake into cells. While a precise cause of diabetes is unknown, genetic factors, environmental factors, and obesity appear to play roles. Diabetics have increased risk in three broad categories: cardiovascular heart disease, retinopathy, and neuropathy. Diabetics may have one or more of the following complications: heart disease and stroke, high blood pressure, kidney disease, neuropathy (nerve disease and amputations), retinopathy, diabetic ketoacidosis, skin conditions, gum disease, impotence, and fetal complications. Diabetes is a leading cause of death and disability worldwide. Moreover, diabetes is merely one among a group of disorders of glucose metabolism that also includes impaired glucose tolerance, and hyperinsulinemia, or hypoglycemia.
Diabetes Prevalence and Trends
Diabetes is an ever more common disease. The World Health Organization (WHO) estimates that diabetes currently afflicts 154 million people worldwide. There are 54 million people with diabetes living in developed countries. The WHO estimates that the number of people with diabetes will grow to 300 million by the year 2025. In the United States, 15.7 million people or 5.9 percent of the population are estimated to have diabetes. Within the United States, the prevalence of adults diagnosed with diabetes increased by 6% in 1999 and rose by 33% between 1990 and 1998. This corresponds to approximately eight hundred thousand new cases every year in America. The estimated total cost to the United States economy alone exceeds $90 billion per year. Diabetes Statistics, National Institutes of Health, Publication No. 98-3926, Bethesda, MD. (Nov. 1997).
Long-term clinical studies show that the onset of complications can be significantly reduced through proper control of blood glucose levels. The Diabetes Control and Complications Trial Research Group, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus, N Eng J of Med, 329:977-86 (1993); U.K. Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes, Lancet, 352:837-853 (1998); and Y. Ohkubo, H. Kishikawa, E. Araki, T. Miyata, S. Isami, S. Motoyoshi, Y. Kojima, N. Furuyoshi, M. Shichizi, Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study, Diabetes Res Clin Pract, 28:103-117 (1995).
A vital element of diabetes management is the self-monitoring of blood glucose levels by diabetics in the home environment. However, current monitoring techniques discourage regular use due to the inconvenient and painful nature of drawing blood through the skin prior to analysis. The Diabetes Control and Complication Trial Research Group, supra. As a result, noninvasive measurement of glucose has been identified as a beneficial development for the management of diabetes. Implantable glucose analyzers eventually coupled to an insulin delivery system providing an artificial pancreas are also being pursued.
Sampling Methodology
A wide range of technologies serve to analyze the chemical make-up of the body. These techniques may be broadly categorized into two groups, invasive and noninvasive. For the purposes of this document, a technology that acquires any biosample from the body for analysis or if any part of the measuring apparatus penetrates into the body, the technology is referred to as invasive.                Invasive: Some examples of invasive technologies for glucose determination in the body are those that analyze the biosamples of whole blood, serum, plasma, interstitial fluid, and mixtures or selectively sampled components of the aforementioned. Typically, these samples are analyzed with electrochemical, electroenzymatic, and/or colorimetric approaches. For example, enzymatic and calorimetric approaches may be used to determine the glucose concentration in interstitial fluid samples.        Noninvasive: A number of approaches for determining the glucose concentration in biosamples, have been developed that utilize spectrophotometric technologies. These techniques include: Raman and fluorescence, as well as techniques using light from the ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm−1), and infrared (2500 to 14,285 nm or 4000 to 700 cm−1)].Noninvasive Glucose Determination        
There exist a number of noninvasive approaches for glucose determination. These approaches vary widely, but have at least two common steps. First, an apparatus is utilized to acquire a signal from the body without obtaining a biological sample. Second, an algorithm is utilized to convert this signal into a glucose determination.
One type of noninvasive glucose determination is based upon spectra. Typically, a noninvasive apparatus utilizes some form of spectroscopy to acquire the signal or spectrum from the body. Utilized spectroscopic techniques include, but are not limited to: Raman and fluorescence, as well as techniques using light from ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm−1), and infrared (2500 to 14,285 nm or 4000 to 700 cm−1)]. A particular range for noninvasive glucose determination in diffuse reflectance mode is about 1100 to 2500 nm or ranges therein. K. Hazen, Glucose Determination in Biological Matrices Using Near-infrared Spectroscopy, doctoral dissertation, University of Iowa (1995). It is important to note that these techniques are distinct from the traditional invasive and alternative invasive techniques listed above in that the interrogated sample is a portion of the human body in-situ, not a biological sample acquired from the human body.
Typically, three modes are utilized to collect noninvasive scans: transmittance, transflectance, and/or diffuse reflectance. For example the signal collected, typically being light or a spectrum, may be transmitting through a region of the body such as a fingertip, diffusely reflected, or transflected. Transflected here refers to collection of the signal not at the incident point or area (diffuse reflectance), and not at the opposite side of the sample (transmittance), but rather at some point on the body between the transmitted and diffuse reflectance collection area. For example, transflected light enters the fingertip or forearm in one region and exits in another region typically 0.2 to 5 mm or more away depending on the wavelength utilized. Thus, light that is strongly absorbed by the body such as light near water absorbance maxima at 1450 or 1950 nm would need to be collected after a small radial divergence and light that is less absorbed such as light near water absorbance minima at 1300, 1600, or 2250 nm may be collected at greater radial or transflected distances from the incident photons.
Noninvasive techniques are not limited to using the fingertip as a measurement site. Alternative sites for taking noninvasive measurements include: a hand, finger, palmar region, base of thumb, wrist, dorsal aspect of the wrist, forearm, volar aspect of the forearm, dorsal aspect of the forearm, upper arm, head, earlobe, eye, tongue, chest, torso, abdominal region, thigh, calf, foot, plantar region, and toe. It is important to note that noninvasive techniques do not have to be based upon spectroscopy. For example, a bioimpedence meter would be considered a noninvasive device. Within the context of the invention, any device that reads a signal from the body without penetrating the skin and collecting a biological sample is referred to as a noninvasive glucose analyzer. For example, a bioimpedence meter is a noninvasive device.
Calibration
Glucose analyzers require calibration. This is true for all types of glucose analyzers such as traditional invasive, alternative invasive, noninvasive, and implantable analyzers. One fact associated with noninvasive glucose analyzers is that they are secondary in nature, that is, they do not measure blood glucose levels directly. This means that a primary method is required to calibrate these devices to measure blood glucose levels properly. Many methods of calibration exist.
One noninvasive technology, near-infrared spectroscopy, requires that a mathematical relationship between an in vivo near-infrared measurement and the actual blood glucose value be developed. This is achieved through the collection of in-vivo NIR measurements with corresponding blood glucose values that have been obtained directly through the use of measurement tools like a HEMOCUE or a YSI (YSI INCORPORATED, Yellow Springs Ohio), or any appropriate and accurate traditional invasive reference device.
For spectrophotometric based analyzers, there are several univariate and multivariate methods that may be utilized to develop the mathematical relationship between the measured signal and the actual blood glucose value. However, the basic equation being solved is known as the Beer-Lambert Law. This law states that the strength of an absorbance/reflectance measurement is proportional to the concentration of the analyte which is being measured, as in equation 1,A=εbC  (1)where A is the absorbance/reflectance measurement at a given wavelength of light, ε is the molar absorptivity associated with the molecule of interest at the same given wavelength, b is the distance that the light travels, and C is the concentration of the molecule of interest (glucose).
Chemometric calibration techniques extract the glucose signal from the measured spectrum through various methods of signal processing and calibration including one or more mathematical models. The models are developed through the process of calibration on the basis of an exemplary set of spectral measurements known as the calibration set and associated set of reference blood glucose concentrations based upon an analysis of capillary blood or venous blood. Common multivariate approaches requiring an exemplary reference glucose concentration vector for each sample spectrum in a calibration include partial least squares (PLS) and principal component regression (PCR). Many additional forms of calibration are known, such as neural networks.
There are a number of reports on noninvasive glucose technologies. Some of these relate to general instrumentation configurations required for noninvasive glucose determination. Others refer to sampling technologies. Those most related to the present invention are briefly reviewed here:
As outlined above, there have been a number of studies documenting the need for an accurate and precise noninvasive glucose analyzer.
R. Barnes, J. Brasch, D. Purdy, W. Lougheed, Non-invasive determination of analyte concentration in body of mammals, U.S. Pat. No. 5,379,764 (Jan. 10, 1995) describe a noninvasive glucose analyzer that utilizes data pretreatment in conjunction with a multivariate analysis to determine blood glucose concentrations.
General Instrumentation:
P. Rolfe, Investigating substances in a patient's bloodstream, UK Patent Application No. 2,033,575 (Aug. 24, 1979) describe an apparatus for directing light into the body, detecting attenuated backscattered light, and utilizing the collected signal to determine glucose concentrations in or near the bloodstream.
C. Dahne, D. Gross, Spectrophotometric method and apparatus for the non-invasive, U.S. Pat. No. 4,655,225 (Apr. 7, 1987) describe a method and apparatus for directing light into a patient's body, collecting transmitted or backscattered light, and determining glucose from selected near-IR wavelength bands. Wavelengths include 1560 to 1590, 1750 to 1780, 2085 to 2115, and 2255 to 2285 nm with at least one additional reference signal from 1000 to 2700 nm.
M. Robinson, K. Ward, R. Eaton, D. Haaland, Method and apparatus for determining the similarity of a biological analyte from a model constructed from known biological fluids, U.S. Pat. No. 4,975,581 (Dec. 4, 1990) describe a method and apparatus for measuring a concentration of a biological analyte such as glucose using infrared spectroscopy in conjunction with a multivariate model. The multivariate model is constructed form plural known biological fluid samples.
J. Hall, T. Cadell, Method and device for measuring concentration levels of blood constituents non-invasively, U.S. Pat. No. 5,361,758 (Nov. 8, 1994) describe a noninvasive device and method for determining analyte concentrations within a living subject utilizing polychromatic light, a wavelength separation device, and an array detector. The apparatus utilizes a receptor shaped to accept a fingertip with means for blocking extraneous light.
S. Malin, G Khalil, Method and apparatus for multi-spectral analysis of organic blood analytes in noninvasive infrared spectroscopy, U.S. Pat. No. 6,040,578 Mar. 21, 2000) describe a method and apparatus for determination of an organic blood analyte using multi-spectral analysis in the near-IR. A plurality distinct nonoverlapping regions of wavelengths are incident upon a sample surface, diffusely reflected radiation is collected, and the analyte concentration is determined via chemometric techniques.
Specular Reflectance:
R. Messerschmidt, D Sting Blocker device for eliminating specular reflectance from a diffuse reflectance spectrum, U.S. Pat. No. 4,661,706 (Apr. 28, 1987) describe a reduction of specular reflectance by a mechanical device. A blade-like device “skims” the specular light before it can impinge on the detector. A disadvantage of this system is that it does not efficiently collect diffusely reflected light and the alignment is problematic.
R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. Pat. No. 5,636,633 (Jun. 10, 1997) describe a specular control device for diffuse reflectance spectroscopy utilizing a group of reflecting and open sections.
R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. Pat. No. 5,935,062 (Aug. 10, 1999) and R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. Pat. No. 6,230,034 (May 8, 2001) describe a diffuse reflectance control device that can discriminate between diffusely reflected light that is reflected from selected depths. This control device may additionally act as a blocker to prevent specularly reflected light from reaching the detector.
Malin et. al., supra describe the utilization of specularly reflected light in regions of high water absorbance such as 1450 and 1900 nm to mark the presence of outlier spectra wherein the specularly reflected light is not sufficiently reduced.
K. Hazen, G. Acosta, A. Abul-Haj, R. Abul-Haj, Apparatus and method for reproducibly modifying localized absorption and scattering coefficients at a tissue measurement site during optical sampling, U.S. Pat. No. 6,534,012 (Mar. 18, 2003) describe a mechanical device for applying sufficient and reproducible contact of the apparatus to the sampling medium to minimize specular reflectance. Further the apparatus allows for reproducible applied pressure to the sampling site and reproducible temperature at the sampling site.
Temperature:
It is well known that many physiological constituents have near-IR absorbance spectra that are sensitive in terms of magnitude and location to localized temperature. This has been reported as impacting noninvasive glucose determinations. Hazen, et. al., supra.
Coupling Fluid:
Index of fraction matching between the sampling apparatus and sampled medium is well known. Glycerol is a common index matching fluid for optics to skin. A number of patents disclose more specific coupling fluids with important sampling parameters.
R. Messerschmidt, Method for non-invasive blood analyte measurement with improved optical interface, U.S. Pat. No. 5,655,530 (Aug. 12, 1997), and R. Messerschmidt Method for non-invasive blood analyte measurement with improved optical interface, U.S. Pat. No. 5,823,951 describe an index-matching medium for use between a sensor probe and the skin surface. The index-matching medium is a composition containing perfluorocarbons and chlorofluorocarbons.
M. Robinson, R. Messerschmidt, Method for non-invasive blood analyte measurement with improved optical interface, U.S. Pat. No. 6,152,876 (Nov. 28, 2000) and M. Rohrscheib, C. Gardner, M. Robinson, Method and apparatus for non-invasive blood analyte measurement with fluid compartment equilibration, U.S. Pat. No. 6,240,306 (May 29, 2001) describe an index-matching medium to improve the interface between the sensor probe and skin surface during spectroscopic analysis. The index-matching medium is preferably a composition containing chlorofluorocarbons. The composition can also contain perfluorocarbons.
T. Blank, G. Acosta, M. Mattu, S. Monfre, Fiber optic probe guide placement guide, U.S. Pat. No. 6,415,167 (Jul. 2, 2002) describe a coupling fluid of one or more perfluoro compounds where a quantity of the coupling fluid is placed at an interface of the optical probe and measurement site. Notably, perfluoro compounds do not have the toxicity associated with chlorofluorocarbons.
Guide:
Blank et. al., supra describe the utilization of a guide in conjunction with a noninvasive glucose analyzer in order to increase precision of the location of the sampled site resulting in increased accuracy and precision in a noninvasive glucose determination.
In all of the related technology of this section, no suggestion of automated analysis is made. Further, no suggestion is made for a fluoropolymer hydration inducer or for a coupling fluid reservoir within the guide. Both of these guide features ease the use of a bioanalyzer such as a near-IR based noninvasive glucose analyzer. In addition, to date no FDA device has been approved for the utilization by an individual or a medical professional for noninvasive glucose concentration determination.
The Problem
Noninvasive glucose analyzers reported to date generally require precision in sampling in order to accurately determine glucose concentrations in the body. The measurement is complicated by every manual step required in the spectral acquisition process utilized in a given glucose determination. Complications include any of a requirement of time, a step requiring manual dexterity, or movement of measurement apparatus that may be bulky, fragile, or sensitive in terms of returned analytical signal. Elimination or automation of steps required for a noninvasive glucose determination is beneficial for at least one of increasing marketability of the analyzer, increasing the number of people who may utilize the analyzer, reduction in time requirements associated with a glucose determination, and increased precision and/or accuracy of a glucose determination. Specifically, preparation of the sampling site in terms of temperature, historesis of applied pressure, hydration, and optical scattering parameters involving actions from the user that may be any of technically challenging, time consuming, and error inducing.
What is desired is a mechanism for reducing user input through methods and apparatus such as a hydration inducer and a coupling agent enhancement integrated into a guide used in conjunction with a noninvasive glucose analyzer.